The LAS studies the molecular biophysical, and integrative bases of associative memory in brain networks. LAS observations have related learning and memory behavior of living animals to signal processing in neuronal networks and to subcellular molecular cascades. Our data have implicated molecular and biophysical mechanisms that are conserved in molluscan and mammalian species and thus could have relevance for human learning and memory. Cellular analyses of associative memory in the snail Hermissenda (Pavlovian/classical conditioning), the rabbit (classical conditioning), and the rat (spatial maze learning, olfactory discrimination) revealed a cascade of cellular and subcellular events during memory formation. These events include: long-term synaptic transformation of GABAergic inhibition into excitation; elevation of intracellular calcium and DAG; translocation of PKC; PKC-mediated phosphorylation of the Ca2+ and GTP-binding protein, cp20 (also called calexcitin): inactivation of voltage-dependent K+ channels; learning- specific regulation of gene transcription; and rearrangement of synaptic terminal branches. Other signaling proteins such as ras have also recently been implicated in longer time domains of memory storage. Such conservation across species suggests that these associative memory mechanisms may provide targets of dysfunction in Alzheimer's disease. LAS scientists have uncovered, for example, Alzheimer-specific defects in K+ channels, IP3-mediated release of CA2+, and metabolism of the G protein, calexcitin. Theoretical constructs derived from brain-based memory networks have also been mathematically described and incorporated into computer-based artificial networks which have demonstrated powerful pattern recognition capabilities. Other molecular biologic tools such as antisense are identifying specific ionic channels on neuronal dendrites that participate in long-term memory. State-of-the-art molecular biologic screening techniques in the LAS have recently implicated new biochemical steps in memory storage. Recent observations have uncovered specific genes that undergo prolonged activation well into the period of memory consolidation. These genes have been confirmed with Northern blot analyses, reverse transcriptase-PCR, and in situ hybridization techniques. One of these memory-related genes encodes the type 2 ryanodine receptor. The ryanodine receptor (RR) is a 450 K calcium channel that has 10 membrane-spanning domains. this receptor is responsible for calcium-mediated calcium release (ClCR) from the endoplasmic reticulum. Very recently LAS studies identified the first known signaling protein that activates the neuronal RR. This protein is calexcitin (cp20) which was previously shown to be phosphorylated by the alpha-isozyme of PKC during associative learning and memory. These and other findings form the basis of a plausible molecular cascade for repeated and prolonged mobilization of intracellular calcium during consolidation of associative memory. Associated training stimuli translocate PKC, activate calexcitin, inactivate voltage-dependent K+ channels on the outer membrane and activate the ryanodine receptor (which shares structural homology with K+ channels) to amplify intraneuronal, and as LAS studies have implicated, intradendritic calcium waves. These sequential molecular events could participate, therefore, in making memory representations in the brain more permanent for later recall.